The present invention generally relates to methods and systems for coating medical devices. Specifically, the present invention relates to systems and methods for automating batch processing of medical devices in a closed system. More specifically, the present invention provides semi-automated methods and systems for coating implantable medical devices with antimicrobials using closed systems that maintain coating solution integrity, increase product throughput and minimizes personnel and environmental exposure to the coating solution.
Localized and systemic infections represent one of the most serious post surgical complications. Over the past fifty years tremendous advances in materials, training and antimicrobial therapies have significantly reduced the number of life-threatening post operative infections. The development of pre-sterilized disposable surgical dressings, medical instruments, gowns, drapes and other materials have helped reduce infection frequency. However, the development of improved antimicrobials represents the single most significant advance in infection control.
There are essentially three categories of antimicrobial agents: antiseptics, disinfectants and antibiotics. Antiseptics are generally defined as compounds that kill or inhibit the growth of microorganisms on skin or living tissue. Antiseptics include, but are not limited to, alcohols, chlorhexidine, iodophors and dilute hydrogen peroxide. Disinfectants are compounds that eliminate pathogenic microorganisms from inanimate surfaces and are generally more toxic, and hence more effective, than antiseptics. Representative disinfectants include, but are not limited to, formaldehyde, quaternary ammonium compounds, phenolics, bleach and concentrated hydrogen peroxide. Antibiotics are compounds that can be administered systematically to living hosts and exhibit selected toxicity, that is, they interfere with selected biochemical pathways of microorganisms at concentrations that do not harm the host. In the alternative, an ideal antibiotic will target specific metabolic pathways that are essential for the parasite, but absent in the host. Antibiotics generally work using one of four basic mechanisms of action: 1) inhibition of protein synthesis; 2) inhibition of cell wall synthesis; 3) interference with nucleic acid synthesis; and 4) altering cell membrane selective permeability. Antibiotics include, but are not limited to penicillins, aminoglycosides, tertacyclines and macrolides.
The fundamental difference between antiseptics, disinfectants and antibiotics is the ability of microorganisms to develop resistance to antibiotics. The characteristics that make antiseptics and disinfectants so effective generally preclude the development of resistant microorganisms. However, disinfectants are unsuitable for use on living tissues and many antiseptics are primarily limited to localized, generally topical, applications. Consequently, most antimicrobial prophylactic and therapeutic regimens rely on antibiotics.
The microorganism""s susceptibility to an antimicrobial and the ability of the antimicrobial to reach the infection site are the two most significant factors that determine antimicrobial therapy efficacy. Antimicrobial susceptibility is generally determined by culturing the organism in the laboratory and testing it against a panel of candidate drugs. However, laboratory testing can only be done if the agent causing the infection is known. When antibiotics are used prophylactically, as is the case with surgical patients, physicians generally prescribe drugs targeted to suppress the growth of the most common post surgical infectious agents. One of the most common organisms associated with surgical infections is Staphylococcus aureus. In the past, penicillin class drugs were considered the drugs of choice to thwart S. aureus infections. However, recently, many new antibiotic resistant microorganisms including penicillin resistant S. aureus have emerged making post surgical infection control even more challenging. Consequently, physicians have turned to new generations of antibiotics in response to emerging resistant strains.
Until recently, methicillin, an analogue of penicillin, was the preferred drug for treating and preventing penicillin resistant S. aureus infections. However, methicillin resistant S. aureus (MRSA) are becoming increasingly more common. Therefore, newer and more effective treatments for MRSA as well as other difficult to treat post surgical infections are in great demand.
One approach to treating and preventing the emergence of antibiotic resistant bacteria such as MRSA is to use two or more antimicrobial compounds in combination. The advantages to this approach include having a second antimicrobial present to inhibit resistant sub-population emergence during treatment and the potential for antimicrobial synergy. Antimicrobial synergy occurs when the efficacy of one antimicrobial is enhanced by another such that the total antimicrobial effect is greater than either one alone. In many cases either antimicrobial used separately may not completely eradicate the infection, but when the drugs are used in combination, powerfully efficacious antimicrobial regimens result.
However, even the most sensitive microorganisms cannot be killed by antimicrobials unless they can reach the infection site (antimicrobial bioavaliablity). Numerous factors determine antimicrobial bioavailablity including route of administration, clearance rates from the body, tissue solubility, and the degree of blood flow surrounding the infected site. Antimicrobials that are susceptible to destruction by digestive fluids, or drugs not easily absorbed in the intestines, must be administer parenterally (usually intravenously). However, regardless of the administration route, the antibiotic must survive circulation through the blood stream prior to reaching the treatment site. If the liver or kidneys rapidly removes an antimicrobial from the blood stream, or if the antimicrobial has a high affinity for blood proteins such that it is bound and inactivated by the blood, its bioavailability can be significantly reduced. This is especially true if the infection site is deep within tissues or organs that have minimal blood flow.
Deep tissue infections can result when medical implants become contaminated prior to surgical placement. When oral or parenterally administered antimicrobials fail to effectively control and eliminate the infection, the medical implant may have to be removed. Removal requires additional surgical procedures to treat the infection and re-implant the device after the infection completely resolves. Moreover, once deep tissue infections are established, long term antimicrobial therapy and hospitalization may be required. These additional procedures increase the costs associated with device implantation, subject the patient to discomfort and in rare circumstances, increase the threat of permanent disfigurement.
Coating implantable medical devices with antimicrobial compounds provides a technique for deep tissue drug delivery that can significantly reduce the risk of post implantation infections. Coating procedures should employ broad spectrum antimicrobials that are effective against most post surgical infections, especially MRSA infections. The antimicrobials need to be soluble in physiological fluids and must be stable enough to survive processing steps required to successfully coat the medical device. Ideally, a synergistic antimicrobial combination should be used. Non-limiting examples of antimicrobial combinations are described in U.S. Pat. Nos. 5,624,704 and 5,902,283, the entire contents of which are herein incorporated by reference. Moreover, the antimicrobial coating procedure must employ methods and materials that are compatible with the antimicrobial and the material used to make the medical device. Medical devices, specifically implantable types, can be fabricated from a wide variety of biocompatible compounds including metals and polymers. Each material presents its own unique challenges to material scientists when it is necessary, or desirable, to coat medical devices with bioactive materials. However, all coating methodologies share common objectives including the need to maximize expensive and labile coating solutions, minimize environmental contamination, provide the medical device with an even coating, and maintain an efficient, controlled process that complies with Federal Food and Drug Administration (FDA) Good Manufacturing Practices (GMP). Tedious manual methods of batch coating medical devices cannot achieve these goals for all medical devices on a consistent basis.
The size, shape and composition of the medical devices can significantly limit manual methods. Moreover, lot-to-lot consistency, GMP compliance and product throughput are all greatly enhanced when automated, or semi-automated, processes are involved. Moreover, non-automated processes subject expensive coating solutions to contamination and excessive waste resulting from spillage and product handling. Additionally, many polymeric compounds used to make medical devices are coated using harsh and often toxic solvent mixtures in order to imbibe the coating material into the devices. Exposure to these solvents poses a potential risk to personal, equipment and the environment that can be best minimized by coating in a closed system, a process incompatible with most manual methods.
Therefore, there is a need for methods and systems that can provide implantable medical devices with antimicrobial coatings. Moreover, there is a need for methods and systems that can provide antimicrobial coatings in a closed system that reduce exposure to toxic solvents, maintain coating solution integrity for prolonged periods, allow for maximum product throughput, provide the medical device with a consistent, even coating, minimize product handling and accomplishes these goals in an FDA GMP compliant manner.
It is an object of the present invention to provide a self-contained, automated system for coating a medical device with an antimicrobial.
It is another object of the present invention to provide antimicrobial coating systems and methods that extend the usable life expectancy (pot life) of the coating solution by limiting the solution""s exposure to atmospheric conditions including light and air.
It is still another object of the present invention to provide antimicrobial coating systems and methods that extend the pot life of the coating solution by minimizing thermal exposure.
It is another object of the present invention to provide antimicrobial coating systems and methods that protect the operator and the environment from the coating solution.
It is yet another object of the present invention to provide antimicrobial coating systems and methods that are automated and minimize user intervention.
It is another object of the present invention to provide implantable medical devices having antimicrobial coatings that reduce post implantation infections by releasing antimicrobial compounds into the surrounding tissues for sustained time periods.
The coating solutions of the present invention are composed of antimicrobial compounds including, but not limited to, antiseptics and antibiotics dissolved in potentially toxic organic solvents. These solutions are extremely expensive to prepare and are easily inactivated by exposure to temperatures above ambient, air (specifically reactive oxygen species), light (specifically ultraviolet light) and contamination. Therefore, maximizing the pot life requires precise temperature control and protection from air, light and contamination. The methods and systems of the present invention accomplish these and other goals and simultaneously reduce the manufacturing environment""s exposure to potentially toxic coating solutions. (at is important to distinguish the coating solutions from coated medical devices. The coating solutions of the present invention are highly concentrated mixtures of antimicrobial compounds and solvents. These mixtures may be toxic to manufacturing professionals exposed to large concentrations. However, the coated medical device, when used in accordance with the manufacturer""s directions for use and under the supervision of a qualified physician, present minimal or no risks to the patient).
The present invention provides methods and systems that permit medical devices to be safely coated with antimicrobial compounds while maximizing pot life. However, the systems and methods of the present invention can be used to coat any device safely and efficiently with a wide range of different compounds and are not limited solely to providing medical devices with antimicrobial coatings.
The use of the term xe2x80x9ccoatingxe2x80x9d is not intended as a limitation and includes any physical or chemical method of providing the surfaces, or polymeric matrices, of medical devices with antimicrobial properties. Non-limiting examples of such chemical and physical methods include impregnation, imbibing, ionic interactions, covalent bonds, van der Waals forces, hydrogen bonding, protein-protein interactions, antibody-antigen complexes, resin coatings, electrodeposition, plasma deposition or the like. Hence the term coating is not to be construed narrowly to mean merely a surface layer, but should be interpreted to include providing a homogeneous concentration or gradient of antimicrobials throughout a medical device""s body.
The present inventors have determined that optimum coating of medical devices occurs when the coating solution is heated to temperatures that significantly accelerate the degradation of the coating solution. In order to optimize the coating process and simultaneously maximize the solution""s pot life, the coating solutions of the present invention are preheated in a holding vessel before being transferred to a processing vessel containing the medical devices. Any coating solution remaining in the holding vessel is cooled to ambient temperatures or below while the processing vessel containing the antimicrobial solution and medical device is held at a constant elevated temperature. At the conclusion of a predetermined optimum processing time, the coating solution is transferred from the processing vessel back to the holding vessel where it is cooled to ambient temperatures or below. This entire process is conducted in a sealed system that protects the coating solution from exposure to damaging environmental factors, reduces solvent evaporation and isolates manufacturing personnel from the solution.
After the medical device has been coated it is aerated for a predetermined time period using a pressurized gas flow (sparging system) and then washed at least once using a wash solution that is pumped into the closed processing vessel and gently agitated using the sparging system of the present invention. After washing is completed, a gas, usually air, is passed over the medical device using the sparger to accelerate the drying process. The device is then removed from the sealed system and packaged prior to terminal sterilization.
The entire process of the present invention is under the control of a programmable microprocessor/controller that receives a series of inputs from remotely located sensors. Each sensor monitors an event and continually notifies the microprocessor/controller of its status. Should any sensor detect an out-of-range condition, the system will either fail to initiate the next step or abort the process while simultaneously notifying an operator of a default situation.
In one embodiment of the present invention the self-contained coating system is attached to a containment platform to collect and confine accidental coating solution spills. Attached to the containment platform is at least one temperature controller consisting of either a heater, a chiller or a combination thereof, a holding vessel, a processing vessel and at least one fluid transfer system. The fluid transfer system moves coating solution between the holding and the processing vessels and/or wash solution to and from the processing vessel. In one embodiment of the present invention there are a plurality of fluid transport systems each directing the flow of different fluids between the holding vessel and processing vessel and/or fluid reservoirs.
In one embodiment of the present invention the holding and processing vessels are fitted with sealable closures and at least one mixing device for maintaining uniform antimicrobial solution and for preventing thermal gradients from forming. The processing vessels of the present invention are also fitted with a sparging system that provides a gas flow into the processing tank during the aeration, washing and drying steps. In one embodiment of the preset invention the gas flow velocity may be adjusted to optimize the particular process step.
In another embodiment of the present invention the antimicrobial coating system includes one or more valve assemblies located at various points along the fluid transfer systems and gas lines. Additionally, numerous sensors may be located on the holding vessel, the processing vessel, vessel closures, the heat transfer devices, the fluid transfer systems, and temperature controllers. Each sensor feeds information to a programmable microprocessor that controls contents, temperatures, fluid levels, and gas flow within the holding and processing vessels. The programmable microprocessor of the present invention can also be adapted to open and close valves and act as a fail-safe monitor responsive to remote sensors.
In another embodiment of the present invention a method for coating a medical device is provided. This method includes providing a sealable first vessel filled with a coating solution and a sealable second vessel containing a medical device to be coated. The coating solution in the first vessel is preheated to a temperature appropriate for the coating process and then transferred to the second preheated vessel. Any coating solution remaining in the first vessel is cooled to at least ambient temperature and the coating solution in the second vessel is held at a constant coating process temperature until the processing interval is complete. At the conclusion of the processing interval the coating solution in the second vessel is transferred back to the first vessel and cooled.
The coated medical device is then aerated, after which the wash solution is transferred into the second vessel and the medical device is washed while gas is gently sparged into the wash solution. After a predetermined period the wash solution is removed and the wash step is repeated as many times as desired. After washing is complete the medical device is dried using a higher velocity of sparged gas. The entire method can be automated by providing a microprocessor/controller responsive to at least one remote sensor.
Other objects and features and advantages of the present invention will be apparent to those skilled in the art from a consideration of the following detailed description of preferred exemplary embodiments thereof taken in conjunction with the Figures which will first be briefly described.